By ovulation, the thickness of the stratum functionalis has been reestablished under the proliferative actions of estradiol-17β (see
Fig. 44.27 ). After ovulation the corpus luteum produces high levels of progesterone along with estradiol-17β. The luteal phase of the ovary switches the proliferative phase of the uterine endometrium to the secretory phase. In general, progesterone inhibits further endometrial growth and induces differentiation of epithelial and stromal cells. Progesterone induces the uterine glands to secrete a nutrient-rich product that supports blastocyst viability. As the secretory phase proceeds the mucosal uterine glands become corkscrewed and sacculated (see
Fig.
44.27 ). Progesterone also induces changes in adhesivity of the surface epithelium, thereby generating the “window of receptivity” for implantation of an embryo (see nancy). Additionally, progesterone promotes differentiation of stromal cells into “predecidual cells,” which must be prepared to form the decidua of pregnancy or to orchestrate menstruation in the absence of pregnancy.
•Fig. 44.28 Molecularmechanismbywhichtheestrogenreceptor(ER)regulatesgeneexpression.Left, Estradiol-17β bindstotheERandchangesitsconformationsothatitbindsasadimertoestrogen-responseelement(ERE)andrecruitscoactivatorproteins(Co-Act),whichleadstostimulationofgeneexpression.Right, Selectiveestrogenreceptormodulators(SERMs),suchastamoxifeninthebreast,alterERconformationsothatitrecruitsco-repressorproteins(Co-Rep),therebyinhibitinggeneexpression.InthiscasetheSERMactsasanERantagonist,butinsometissuesthesameSERMcanactasanERagonist.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.)
Progesteroneopposestheproliferativeactionsofestradiol-17β anddownregulatestheestrogenreceptor(ER).Progesteronealsoinducesinactivating isoforms of 17β-HSD, therebyconvertingtheactiveestradiol-17β intotheinactiveestrone.Thisoppositionofthemitogenicactionsofestradiol-17β byprogesteroneisimportanttoprotecttheuterineendometriumfromestrogen-induceduterinecancer.Incontrast,administrationof“unopposed estrogen” towomensignificantlyincreasestheriskforuterinecancer.
Fig.44.28 ).Forexample,theSERMtamoxifen isusedasanERantagonistforthetreatmentofbreastcancer(whoseearlyprogressionispromotedbyestrogen).BindingofSERMtotheERinducesconformationalchangesthatallowco-repressorstobindtotheERorpromotedegradationoftheER(orboth;see
Fig.
44.28 ).Becausetamoxifenhassomeuterotropicactivity(i.e.,makesuterineendometrialtissuegrow),newerSERMssuchasraloxifene havebeendevelopedtohaveERantagonistactivityonthebreast,beneficialERagonistactivityonbone(seelater),andnoactivityorERantagonisticactivityontheuterineendometrium.
In a nonfertile cycle, death of the corpus luteum results in sudden withdrawal of progesterone, which leads to changes in the uterine endometrium that result in loss of the lamina functionalis (see Fig. 43.27). Menstruation normally lasts for 4 to 5 days (called a period), and the volume of blood loss ranges from 25 to 35 mL. Menstruation coincides with the early follicular phase of the ovary.
Hormonal Regulation of the Myometrium